The human papillomavirus (HPV) is a small, uncoated, double-stranded DNA virus that infects through the surface of skin and mucosa and is implicated to a variety of diseases. Skin HPV infection may cause verrucae on the hand or foot that can persist for months to years. Such a benign pathological change is generally not life-threatening except for rare cases, but may cause pain to the patient. Mucosal HPV infects the regions of the anus and the genital as well as the oral cavity. Nearly 100 different types of HPV have been identified up to date. Almost 40 subtypes of HPV specifically infect the genital system and the mucous membranes of the oral cavity. These types of HPV will not induce any symptoms upon infection and rarely give rise to visible genital verrucae, while the symptoms typically are gradually manifested after 2-3 months with viral infection. Infection may not be known until 3 weeks to several years later, therefore HPV spreads unknowingly. Most of the occurrences of infection is asymptomatic, but may lead to genital verrucae and cancers of the anus and the genital tract. The genital verrucae resulting from mucosal HPV infection is considered as one of a number of sexually transmitted diseases (STD), and its occurrence worldwide being two times that of herpes simplex virus infection. Persistent HPV infection may lead to a premalignant lesion—cervical intraepithelial neoplasia (CIN), some cases of which may develop into cervical cancer. Cervical cancer has a very high occurrence in the world, most cases of which are detected positive for HPV 16 and HPV18 DNA (>99%). Cervical cancer has a morbidity of 9.98 in 100 thousand people, resulting in an increase of 500,000 patients throughout the world each year, and is the most significant causative factor of death of women under the age of 50. Besides cervical cancer, HPV is also implicated in many anal and perianal cancers.
The preventive vaccine has been developed at present. Major capsid protein for HPV has been expressed in eukaryotic cells and it can form virus-like particles (VLPs) in the expression host. Purified VLPs are useful as effective preventive vaccine against HPV infection. However, there are no available effective therapeutic compositions yet for curing such infection. Since the virus makes use of many of the host's own mechanisms for its replication, it is difficult to develop a drug that inhibits viral replication without harming the host. It is known that the immune system plays an important role in controlling HPV infection. The fact of increase in the possibility of HPV infection among people having received immunosuppressive treatment also demonstrates the control over viral infection by the immune system. The researches on the abatement of naturally-occurring verrucae also show evidences of the ability of the immune system to curb infection. The natural abatement of some external genitalia verrucae would happen in some subjects. Histological studies have shown the occurrence of a significant numbers of T lymphocytes in the afflicted area, leading to the assumption that the effective immune response against HPV infection is mainly mediated by cellular immunity. Moreover, natural abatement of verrucae is associated with lymphocyte infiltration, titillation, rubefacientness in the infection area and other symptoms relevant to cell-mediated immune responses. HPV infection followed by induction of lesions is commonly seen in patients with impaired cell-mediated immunity. Therefore, the induction of effective cell-mediated immune responses against HPV antigens is key to the development of vaccine against HPV infection.
The studies on preventive vaccine focus on L1 protein. This protein can effectively activate organisms to generate strong and persistent humoral immunity, allowing for the efficacious prevention of certain subtypes of HPV infection, but it is not effective for the treatment of lesions following HPV infection. E6 and E7, two HPV proteins that can induce and maintain cell transformation, are expressed in the HPV-infected tumor cells and are ideal therapeutic targets. Therefore, therapeutic compositions directed to E6 and E7 provide options for controlling the diseases associated with HPV infection. By using suitable antigen presenting systems (or antigen carriers), E6 and E7 or determinants thereof can be presented to the host to induce strong, long-lasting and specific cell-mediated immune responses, which may cure the diseases associated with HPV infection.
The HPV L1 and L2 capsid protein has been used as the carrier system for transporting HPV E6 or E 7 protein antigens to induce cell-mediated immune responses. Immune tolerance to HPV may be induced in the host due to certain immunity to HPV that the infected host possesses, or due to the latency or persistent infection of HPV in the infected host. In fact, although HPV capsid protein has potential immunogenicity, only half of the patients with cervical cancer can generate immunoglobin G (IgG) specific for the capsid protein. Such a pre-existing immunity or immune tolerance caused by HPV L1 or L2 capsid protein may restrict the efficacy of therapeutic vaccine.
When recombinantly expressed in a suitable expression system, capsid proteins derived from other viruses are also capable of self-assembly into VLPs in a suitable host. These VLPs can also be used as the antigen presenting systems (or antigen carriers) for presenting E6 or E7 antigens or determinants thereof to induce cell-mediated immune responses. However, the purification of the VLPs is still a concern. If VLPs are derived from viruses whose host is human, the resulting therapeutic vaccine also faces the problem of immune tolerance.
Accordingly, there is a need in the art to provide a therapeutic composition for treating the diseases associated with HPV infection.